Assessment of Normal, Normal Variants, and Precocious Puberty in Children Referred with Signs of Early Pubertal Development to a Pediatric Endocrine Unit

HAYDARPAŞA NUMUNE MEDICAL JOURNAL

DOI: 10.14744/hnhj.2019.53765 Haydarpasa Numune Med J 2019;59(1):71–77

ORIGINAL ARTICLE hnhtipdergisi.com

Assessment of Normal, Normal Variants, and Precocious Puberty in Children Referred With Signs of Early Pubertal Development to a Pediatric Endocrine Unit

Suna Kılınç Department of Pediatric Endocrinology, University of Health Sciences Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey

Abstract Introduction: The aim of this study was to evaluate the etiologic distribution and clinical features of children referred to a pediatric endocrinology clinic with signs of early puberty, and to compare clinical, biochemical, and anthropometric properties of the patients followed-up with the diagnosis of precocious puberty and normal variants puberty. Methods: In this single-center study, we included children referred with signs of early puberty between July 2015 and July 2017. We retrospectively evaluated the anthropometric measurements and pubertal status of the patients. In the evaluation of patients with suspected early puberty, biochemical tests, bone age, and pelvic ultrasound were used. If indicated, a standard gonadotropin-releasing hormone stimulation test and brain magnetic resonance imaging were performed. Results: A total of 476 children were referred for evaluation of early puberty. There were 454 (95.3%) females. The mean age of the patients at the time of referral was 8.97±2.5 years for girls and 9.56±0.74 years for boys. Out of 476 children, only 139 (29.2%) had early pubertal development, and the remaining 337 (70.8%) had normal puberty or no puberty. Out of 139 patients, 45 (9.4%) had precocious puberty, 59 (12.3%) had premature thelarche, and 35 (7.3%) had premature adrenarche. Discussion and Conclusion: Most of children referred for the evaluation of early pubertal development showed normal puberty or puberty variants. This study emphasizes the importance of a good diagnostic evaluation of these patients. Keywords: Precocious puberty; premature adrenarche; premature thelarche; puberty.

uberty is a transitional period from childhood to adult- fluenced by many ethnic, nutritional, and environmental Phood in which primary and secondary sex characteris- factors [4]. tics, sexual maturation, and reproductive ability develop Precocious puberty is defined as the breast development [1,2]. As a result of the hypothalamus-pituitary-gonadal before the age of 8-years-old or menarche before the age of (HHG) axis activation, the onset of the pulsatile secretion 10-year-old in girls, and is defined as the testicular volume of gonadotropin-releasing hormone (GnRH) is the main above 4 mL according to the Prader orchidometer before mechanism that initiates puberty [3]. The onset and tempo the age of 9-years-old in boys [5,6]. Premature thelarche and of puberty is inherent to the individual and is managed by premature adrenarche are considered normal variants of complex neuroendocrine–genetic mechanisms and is in- puberty. Premature thelarche is the occurrence of isolated

Correspondence (İletişim): Suna Kılınç, M.D. Saglik Bilimleri Universitesi Istanbul Bagcilar Egitim ve Arastirma Hastanesi, Cocuk Endokrinolojisi Anabilim Dali, Istanbul, Turkey Phone (Telefon): +90 212 440 40 00 E-mail (E-posta): [email protected] Submitted Date (Başvuru Tarihi): 30.01.2019 Accepted Date (Kabul Tarihi): 11.02.2019 Copyright 2019 Haydarpaşa Numune Medical Journal This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). 72 Kılınç, Early Puberty / doi: 10.14744/hnhj.2019.53765

breast development before the age of 8-years-old (gener- were calculated. Using appropriate formulas, the targeted ally before the age of 2-years-old), without any other signs height was calculated for the girls as (the mother height + of puberty. Premature adrenarche is an early pubic and/or father height − 13)/2 and for the boys as (the mother height axillary hair growth before the age of 8-years-old in girls and + father height + 13)/2. Pubertal staging was determined ac- 9-years-old in boys without any other signs of puberty [7,8]. cording to the Marshall and Tanner method [12,13]. Patients’ Early pubertal disorders are common complaints for admis- left wrist radiograms were obtained and bone ages were sion to pediatric outpatient clinics. Most of the applications determined according to the Greulich and Pyle method. The consist of subjects with normal puberty variants. There is PAH of the patients older than 6-years-old was calculated us- [14] no need to treat these cases, as it has been determined that ing the Bayley–Pinneu method . there is no effect on the final adult height in long-term fol- In the evaluation of the patients with suspected early pu- low-up [9]. However, their clinical follow-up is important. berty hormonal tests were obtained. The levels of folli- In cases of early and rapidly progressive puberty, early cle-stimulating hormone (FSH), luteinizing hormone (LH), menarche in girls and final height below the genetic poten- estradiol (E2), free-thyroxin (fT4), and thyroid stimulating tial due to an early epiphyseal closure in both genders are hormone (TSH) , total testosterone (TT), dehydroepiandros- observed [1,10]. Early puberty has negative psychosocial ef- terone-sulfate (DHEA-S), and 17 hydroxyprogesterone (17- fects, as well as physical effects on the child, and this causes OHP) levels were measured. LH, FSH, E2, TT, and DHEA-S anxiety in the parents [1]. Therefore, treatment of early pu- levels were measured using ICMA method kits (Cobas 6000 berty is a multifaceted treatment with clinical and psycho- analyzer series, Roche Diagnostics, USA). The 17-OHP level logical aspects. The aim of the treatment is to prevent the was measured by LC-MS/MS (Agilent-6460 System). loss of adult height and to stop the pubertal development, The baseline LH of >0.3 mIU/mL and E2 of >12 pg/mL in as well as to prevent psychological stress and emotional girls were evaluated in favor of the onset of puberty [1,2]. problems that may be caused by precocious puberty. The dimensions of the uterus, uterine volume, endometrial The aim of this study was to determine the diagnostic dis- thickness, corpus-to-cervix ratio, ovarian size, and ovarian tribution and clinical characteristics of patients that were follicles and their size were evaluated. On ultrasonography, referred to the endocrine outpatient clinic with signs of the long axis of uterus (≥35 mm), corpus-to-cervix ratio early pubertal development, to compare the biochemical (≥1), and ovarian volume (≥2 mL) were evaluated in favor [15,16] and anthropometric properties of patients with precocious of the onset of puberty . puberty and normal variant puberty, and to determine the In cases where distinction between precocious puberty clinical findings of patients who were followed-up and in- and premature thelarche could not be made based on the cluded in a therapeutic regimen. baseline values, GnRH-stimulation test results were used. For the GnRH-stimulation test, 2.5 μg/kg (max 0.1 mg) Materials and Methods GnRH (Gonadorelin acetate, Ferring®) was intravenously This study approved by the Ethics Committee of University administered. After that, blood samples were taken at 30, of Health Science İstanbul Bağcılar Education and Research 60, and 90 minutes, and the LH, FSH and E2 measurements Hospital (No: 2017.10.2.02.003). The data of the patients were repeated. The stimulated LH level of >5 mIU/mL was [17] who referred to our pediatric endocrine clinic between July evaluated as pubertal response . 2015 and July 2017 with the suspicion of early pubertal de- In all male patients diagnosed with central puberty, and in all velopment were retrospectively reviewed from the patient girls under 6 years of age, contrast-enhanced pituitary mag- records and patient registration forms. netic resonance imaging (MRI) was performed to determine The stage of puberty determined by physical examination etiology. MRI of the pituitary gland was performed in girls [18,19] and the height, weight, targeted height, predicted adult aged 6–8 years if there was only a neurological finding . height (PAH), bone age, and biochemical tests were evalu- Precocious puberty was defined as an onset of breast ated. The body weight of the patients was measured with a development before the age of 8 years associated with Seca brand digital scale, and the height of the patients stand- one or more than one relevant symptoms (menstruation, ing at a neutral position was measured with a Seca brand sta- growth of pubic/axillary hair, bone age older than 2 SDSs diometer mounted on the wall. Body mass index (BMI) was of chronological age), increases in the gonadotropin (LH, calculated using the weight (kg)/height (m)2 formula [11]. FSH) and/or sex steroid hormone (E2 in girls) levels, and The height, weight and BMI standard deviation scores (SDS) a LH dominant response (peak LH/FSH ratio >0.66) to the Kılınç, Early Puberty / doi: 10.14744/hnhj.2019.53765 73

GnRH test. Premature thelarche was defined as breast de- could not differentiate among with precocious puberty. velopment before the age of 8 years without any other The mean age of the patients diagnosed with premature signs of puberty, and premature adrenarche was defined as adrenarche was 6.97±0.78 years. The complaints started at pubic and/or axillary hair growth before the age of 8 years a mean duration of 6.2±9.5 months. In terms of etiology, in girls and before the age of 9 years in boys without any there were no underlying causes of premature adrenarche. other signs of puberty. Infantile pubic hair was defined as The characteristics of the cases diagnosed with precocious isolated pubic hair without any other findings of puberty in puberty, premature thelarche, and premature adrenarche boys and girls <1 year of age. are presented in Tables 2, 3, and 4. Statistical Analysis Table 1. Diagnostic distribution and clinical characteristics of The data were analyzed using the Statistical Package for the patients that were referred with the suspicion of early pubertal Social Sciences (SPSS) (Version 17, Chicago IL, USA). Descrip- development tive statistics for discrete and continuous variables were ex- Diagnosis n (%) Female/Male pressed in terms of the mean, standard deviation, median value, minimum, maximum, numbers, and percentages. Normal puberty or no puberty 337 (70.8) 319/18 Early pubertal disorder 139 (29.2) 135/4 Results Precocious puberty 45 (9.4) 44/1 <8 years 33 (6.9) 32/1 Between July 2015 and July 2017, a total of 476 patients >8 years 12 (2.5) 12/0 were referred to our outpatient clinic with the suspicion of Premature thelarche 59 (12.3) 59/0 early pubertal development. Twenty-two (4.6%) patients <8 years 59 (12.3) 59/0 were male, and 454 (95.3%) of them were female. The male- >8 years 0 (0) 0 to-female ratio was 20:1. The mean age at the admission Premature adrenarche 35 (7.3) 32/3 was 8.97±2.5 years for female and 9.56±0.74 years for male <8 years 31 (6.5) 28/3 patients. Only 139 (29.2%) patients were diagnosed with >8 years 4 (0.8) 4/0 early pubertal disorder. The characteristics and diagnostic distributions of the cases are presented in Table 1. Table 2. Clinical and biochemical characteristics of girls with Four patients with early pubertal disorder were male, and precocious puberty 135 were female. The female-to-male ratio was 33:1. In Mean SD Confidence males, 1 patient had precocious puberty, and 3 patients had Interval 95 % premature adrenarche. In females, 44 (32.5%) patients had Lower Limit Upper Limit precocious puberty, 59 (43.7%) patients had premature thelarche, and 32 (23.7%) patients had premature adrenarche. Age (year) 7.68 0.83 7.43 7.93 Height (cm) 129.7 8.8 127.0 132.4 The mean age of the female patients with the diagnosis of Height SDS 0.88 1.29 0.49 1.27 precocious puberty was 7.68±0.83 years. The complaints Weight (kg) 30.6 7.5 28.3 32.9 started at a mean duration of 7.8±8.2 months. Twelve pa- Weight–SDS 0.86 1.24 0.48 1.24 tients were older than 8 years, 2 of them developed pre- BMI–SDS 0.58 1.10 0.24 0.91 cocious puberty due to non-classical congenital adrenal HA 8.47 1.56 8.00 8.95 BA 9.75 1.54 9.28 10.22 hyperplasia (NCCAH), 2 of them were admitted because of MPH 158.3 4.2 156.5 160.1 menarche, and 8 of them had signs of puberty before the MPH–SDS −0.71 0.68 −0.99 −0.42 age of 8, but with late applications. All patients under the PAH 152.9 6.05 150.4 155.4 age of 8 years underwent pituitary MRI. Three patients had LH (IU/L) 0.91 1.17 0.55 1.26 microadenoma, 1 patient had arachnoid cyst, and 1 pa- FSH (IU/L) 2.29 0.94 2.01 2.58 tient had rathke cleft cyst. In all patients under the age of 8 E2 (pg/mL) 6.65 5.22 5.07 8.24 Peak LH (n=32) 8.99 6.39 6.60 11.37 years, idiopathic central precocious puberty was detected. Peak-FSH (n=32) 12.77 4.50 11.09 14.45 The mean age of the patients with premature thelarche Pik LH/FSH 0.75 0.48 0.67 0.93 was 4.4±2.61. The complaints started at a mean duration SD: standard deviation; SDS: standard deviation score; BMI: body mass of 8.2±10.1 months. Thirty-seven patients (62%) were index; HA: height age; BA: bone age; MPH: mid-parental height; PAH: younger than 4 years. The GnRH tests were performed in 17 predicted adult height; LH: luteinizing hormone; FSH: follicle-stimulating hormone; E2: estradiol. (28%) patients in whome clinical and laboratory findings 74 Kılınç, Early Puberty / doi: 10.14744/hnhj.2019.53765

Table 3. Clinical and biochemical characteristics of girls diagnosed Table 5. Characteristics of patients with no early pubertal disorder with premature thelarche Diagnosis n (%) F/M The indication of Mean SD Confidence application or referral Interval 95% Lipomastia 22 (6.5) 22/0 Breast development Lower Limit Upper Limit Infantil pubik hair 6 (1.7) 2/4 Pubik hair Age (years) 4.40 2.61 3.72 5.08 Urinary tract infection 2 (0.5) 2/0 Premature menarche Height (cm) 102.6 21.26 96.92 108.00 Menarche 14 (4.1) 14/0 Premature menarche Weight (kg) 17.98 6.59 16.26 19.69 (normal puberty) Height SDS -0.02 0.76 -0.22 0.18 Obesity/overweight 40 (11.8) 40/0 Accelerated somatic Weight–SDS 0.27 0.74 0.08 0.46 growth; advanced BMI–SDS 0.41 0.96 0.16 0.66 bone age HA 4.49 2.79 3.76 5.21 No puberty 21 (6.2) 21/0 Accelerated somatic BA 4.49 3.00 3.71 5.27 growth MPH 158.3 4.87 151.24 159.77 Normal puberty 231 (68.5) 218/14 Suspicion of MPH–SDS -0.72 0.92 -1.02 -0.47 precocious puberty PAH (n=25) 156.0 5.04 150.44 157.43 LH (IU/L) 0.52 0.57 0.37 0.66 F: female; M: male. FSH (IU/L) 2.95 1.69 2.51 3.39 E2 (pg/mL) 5.73 3.18 4.89 6.56 Among patients who were not considered as having early Peak LH (n=17) 3.61 1.20 3.03 4.18 pubertal disorder, 22 patients were referred for breast de- Peak-FSH (n=17) 15.16 4.11 13.18 17.14 velopment, but lipomastia was detected during physical Peak LH/FSH 0.24 0.09 0.20 0.29 examination. Two patients were referred due to premature SD: standard deviation; SDS: standard deviation score; BMI: body mass menarche, but urinary tract infection was detected in both index; HA: height age; BA: bone age; MPH: mid-parental height; PAH: predicted adult height; LH: luteinizing hormone; FSH: follicle-stimulating patients, and premature menarche was not considered. hormone; E2: estradiol. Fourteen patients presented with an early-onset menstrual period, but all were older than 10 years. Twenty-six patients Table 4. Clinical and biochemical characteristics of girls with the who were referred for early pubertal disorder due to an diagnosis of premature adrenarche accelerated somatic development were obese, and 14 pa- Mean SD Confidence tients were overweight. The characteristics of the patients Interval 95% with no early pubertal disorders are presented in Table 5. Lower Limit Upper Limit Discussion Age 6.97 0.78 6.69 7.25 Height (cm) 122.27 5.36 120.33 124.20 In this single-center retrospective study 476 patients ad- Height SDS 0.27 0.81 -0.02 0.56 mitted/referred to our clinic with the query of early puberty Weight (kg) 26.96 5.51 24.98 28.95 but only 139 (29%) of these patients had early pubertal dis- Weight–SDS 0.83 1.09 0.44 1.22 orders. Additionally, only 45 (9.4%) of these patients had BMI–SDS 0.80 1.13 0.40 1.21 precocious puberty that requiring treatment. In this study, HA 7.25 0.93 6.91 7.58 the number of patients that were admitted/referred with BA 7.90 1.32 7.42 8.38 the suspicion of early puberty is very high. This shows that MPH 158.2 5.41 154.5 161.4 it is not easy to evaluate the pubertal process even if it is MPH–SDS -0.72 0.89 -0.97 -0.34 normal. Because of individual differences due to the effects PAH 157.90 6.05 152.40 158.40 of many factors affecting growth and puberty, evaluation DHEA-S (µg/dL) 88.42 38.18 74.65 102.18 of the normal course of the pubertal process requires ad- TT (ng/mL) 0.025 0.00 0.025 0.025 equate experience and sufficient social pediatric practices. 17-OHP (ng/mL) 0.23 0.23 0.14 0.31 Similar studies in the literature were examined. Among [20] SD: standard deviation; SDS: standard deviation score; BMI: body mass them Kaplowitz et al. examined 104 patients present- index; HA: height age; BA: bone age; MPH: mid-parental height; PAH: ing with early pubertal symptoms. Their study population predicted adult height; DHEA-S: dehydroepiandrosterone-sulfate; TT: total mostly consisted of female cases (87% females vs. 13% testosterone; 17-OHP: 17-hydroxyprogesterone. males). Here, precocious puberty was detected in 9%, pre- Kılınç, Early Puberty / doi: 10.14744/hnhj.2019.53765 75

mature thelarche in 18%, premature adrenarche in 46% of the last few years, in many publications, it has been asso- patients. Although the rate of female applicants was signif- ciated with components of the metabolic syndrome, such icantly higher (7:1) than the rate of male applicants in their as hypertension, dyslipidemia, and insulin resistance [29]. In study, the ratio of female-to-male applicants (20:1) was our study, normal variants of puberty that did not require found to be much higher in our study. This may be related to any treatment was detected in 19.6% of the patients. The the difference between the number of patients presenting ratio of normal variants of puberty in our study was consis- to two studies. The rate of precocious puberty in the same tent with the literature [17,21]. study was similar to our study, but a significantly higher There has been an increase in the incidence and prevalence number of patients were diagnosed as premature adrenar- of precocious puberty as reported in various publications. che in comparison to our study. In a similar study with 449 In a study conducted in Korea, the prevalence of preco- female patients who were recently treated by Mogensen cious puberty was reported as 55.9 in 100.000 girls [30]. In [17] et al., 19.5% of the applicants were evaluated as preco- various studies, 86%–92% of the cases of precocious pu- cious puberty, 1.3% as peripheral precocious puberty, 15% berty consisted of female children with a female-to-male as premature thelarche, and 10% as premature adrenarche. ratio ranging from 3:1 to 23:1[31]. However, in our study this In this study, the diagnostic rates of premature thelarche rate was 33:1, and 97.2% of the cases were female patients. and premature adrenarche diagnosis were similar to our Our higher rate can be explained by genetic and environ- [21] study. In Turkey, Eklioğlu et al. very recently examined mental factors. The mean age at the diagnosis was 7.5 years only female patients, and detected precocious puberty in in precocious puberty consistent with the literature [32]. 8.3%, premature thelarche in 14.6%, premature adrenarche Precocious puberty is divided into three categories: go- in 4.2%, and premature menarche in 3.1% of their patients. nadotropin dependent (central); gonadotropin indepen- The study group consisted of patients aged over 8 (69.8%) dent (peripheral); and combined (central and peripheral) and below 8 years of age (30.2%). These rates are similar to [6]. In a study by Cisternino et al. [33] including 438 female those in our study. Differences in studies in terms of distri- children, the patients were diagnosed as central preco- bution of diagnoses may be due to diversities in the num- cious puberty (97.7%) and peripheral precocious puberty ber of cases, environmental factors, socio-cultural reasons, (2.3%). In our study, we detected NCCAH related periph- ethnic origin, and genetic differences. eral precocious puberty in 2 (4.5%) girls. The remaining 42 The suspicion of early pubertal disorders is one of the most (95.4%) patients had gonadotropin-dependent (central) common causes of admission to pediatric endocrine out- precocious puberty. patient clinics. Most of the applications are normal variants of puberty [17,20,21]. The frequency of the normal variants of Cranial MRI is recommended to rule out the intracranial puberty differs in each community, and it is quite frequent. pathology in patients with central precocious puberty. The In the study by Atay et al.[22] in Turkey, the prevalence rates prevalence of hypothalamo-pituitary lesions was found to of premature thelarche and premature adrenarche were be higher in boys with central precocious puberty (40%– [34] 8.9% and 4.5%, respectively, in girls under 8 years of age. 90%), while this rate was reported to be 8%–33% in girls . Premature thelarche is especially seen between 2 and 4 In girls whose pubertal symptoms started after 6 years of [34] years of age and is defined as isolated breast development age, its prevalence is approximately 2% . In addition to without the acceleration of growth and progression in the the pathological findings in cranial MRI, incidental findings [34] bone age [23]. These cases have a normal growth tempo, that do not mean any importance are also encountered . bone ages are not advanced, the ovarian and uterine vol- These findings may cause unnecessary stress in the family umes are in prepubertal size and a FSH dominant response and the patient, and may lead to unnecessary and poten- is received in a GnRH test. These patients did not have to be tially harmful interventions to be performed in the patient. treated, and it was found that there were no effects on the These findings, which are not associated with central pre- final adult height during the long-term of follow-up. While cocious puberty, have been reported to be 11% in the lit- [34] in 60% of the cases clinical findings regress, 14%–19% of erature . In our study, the rate of these incidental finding the cases may progress to precocious puberty [20,24–26]. was found to be 15% in patients with central precocious Premature adrenarche is characterized by pubic hair, axil- puberty. The most common incidental finding was pitu- lary hair, adult-type sweat, and acne as the result of an early itary microadenoma. increase in the secretion of adrenal gland androgen (espe- Rapid growth in precocious puberty, increase in the skele- cially DHEA-S) due to hitherto unknown etiologies [27,28]. In tal maturation rate, and progression of the bone age have 76 Kılınç, Early Puberty / doi: 10.14744/hnhj.2019.53765

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